Metabolic Hijacking: An MOF-Based Nanoprogrammer Overcomes Drug Resistance in Glioblastoma

Glioblastoma (GBM) is one of the deadliest solid cancers
with limited
treatment options. Resistance to Temozolomide (TMZ), the most common
oral anticancer drug available for GBM, develops rapidly and frequently
in patients. This study reveals TMZ-sensitive GBM cells rely on glycolysis,
while resistant counterparts preferentially utilize fatty acid oxidation
(FAO). Hence, we developed an engineered nanoprogrammer using a metal–organic
framework (MOF) coloaded with TMZ and the FAO inhibitor (etomoxir,
ETO). Postengineered unsaturated Fe3+ sites adsorbed transferrin,
enabling efficient blood–brain barrier traversal and tumor
targeting. TMZ suppressed aggressive tumor growth by eliminating glycolysis-dependent
cells during early treatment. Simultaneously, ETO inhibited FAO in
resistant cells, forcing metabolic rewiring to glycolysis and restoring
TMZ susceptibility. This dual-action strategy disrupted energy pathways
in heterogeneous tumors, overcoming resistance. The nanoprogrammer
demonstrated potent efficacy in orthotopic and patient-derived drug-resistant
GBM models, achieving significant tumor suppression without notable
toxicity.

胶质母细胞瘤（Glioblastoma, GBM）是致死率最高的实体恶性肿瘤之一，治疗选择极为有限。替莫唑胺（Temozolomide, TMZ）是目前临床用于GBM的最常用口服抗肿瘤药物，但患者体内极易快速产生耐药性。本研究发现，对TMZ敏感的GBM细胞依赖糖酵解供能，而耐药细胞则优先利用脂肪酸氧化（FAO）途径。据此，我们开发了一种工程化纳米编程载体：采用金属有机框架（MOF）共负载TMZ与FAO抑制剂依托莫司（etomoxir, ETO）。该载体经工程改造后，其不饱和Fe³⁺位点可吸附转铁蛋白，从而实现高效穿越血脑屏障并靶向肿瘤组织。TMZ可在治疗早期通过清除依赖糖酵解的肿瘤细胞抑制恶性增殖；与此同时，ETO可抑制耐药细胞的FAO途径，迫使细胞代谢重编程转向糖酵解，进而恢复其对TMZ的敏感性。这种双重作用策略可靶向异质性肿瘤的能量代谢通路，克服肿瘤耐药性。该纳米编程载体在原位移植及患者来源耐药GBM模型中展现出强效抗肿瘤活性，可显著抑制肿瘤生长且未观察到明显毒性。